This invention relates to stabilized aqueous aminophylline solutions. More particularly, it relates to a process and stabilized aminophylline solution wherein disodium edetate is added to the solution as a chelating agent in a preferred amount of 0.01 to 1.0% by weight and carbon dioxide is removed from the aqueous aminophylline solution so as to substantially prevent crystal growth in the aminophylline solution when it is packaged in a ready-to-use container system.
Aqueous aminophylline solutions are useful in I.V. administration as diuretics, cardiotonics and as respiratory stimulants. In the past, this product has not been prone to exhibit instability when packaged in a single-dose ampoule. Recently, however, demands for ready-to-use packaging and emergency drug solutions such as ready-to-use vials and syringes tend to promote undesired crystal growth. This crystal growth is totally unacceptable from the standpoint of efficacy, pharmaceutical elegance, possible loss of potency and the safety required of all parenterals. The crystal information has been found to be a function of an interaction between the drug and stopper. The growth of the crystals is not a function of stopper incompatability, but instead a chemical phenomenon due to the ability of the disassociated drug to complex with divalent ions available in the stopper. This is supported by the observation that the crystals developed in the packaging system in question first occur at the solution - stopper interface.
The U.S. Pharmacopeia advises as to the avoidance of carbon dioxide in containers for aminophylline. An article entitled "Antioxidants and Chelating Agents as Stabilizers in Liquid Dosage Forms" by Leon Lachman in Drug and Cosmetic Industries, Vol. 102, page 43 (February, 1968), as the title implies, utilizes antioxidants and chelating agents to enhance the stability of pharmaceutical liquids. However, it should be pointed out that quite unexpectedly it was found that a compound closely chemically related to the chelating of this invention, calcium disodium edetate, will not prevent crystal development in a container system for aqueous aminophylline, where metal ions are present.
It is an advantage of the present invention to provide a stabilized aminophylline aqueous solution and a method for providing such solution. Other advantages are a stabilized aqueous aminophylline solution which can be packaged in ready-to-use stoppered vials wherein crystal growth of the solution as effected by the stopper is eliminated, an aqueous aminophylline solution which when packaged in a stoppered container will maintain efficacy, pharmaceutical elegance, high potency and safety for the parenteral solution.